Molecular basis for the inhibition of the methyl-lysine binding function of 53BP1 by TIRR

Nature Communications
Jiaxu WangXiuhua Liu

Abstract

53BP1 performs essential functions in DNA double-strand break (DSB) repair and it was recently reported that Tudor interacting repair regulator (TIRR) negatively regulates 53BP1 during DSB repair. Here, we present the crystal structure of the 53BP1 tandem Tudor domain (TTD) in complex with TIRR. Our results show that three loops from TIRR interact with 53BP1 TTD and mask the methylated lysine-binding pocket in TTD. Thus, TIRR competes with histone H4K20 methylation for 53BP1 binding. We map key interaction residues in 53BP1 TTD and TIRR, whose mutation abolishes complex formation. Moreover, TIRR suppresses the relocation of 53BP1 to DNA lesions and 53BP1-dependent DNA damage repair. Finally, despite the high-sequence homology between TIRR and NUDT16, NUDT16 does not directly interact with 53BP1 due to the absence of key residues required for binding. Taken together, our study provides insights into the molecular mechanism underlying TIRR-mediated suppression of 53BP1-dependent DNA damage repair.

References

Nov 5, 1999·Molecular Cell·M E MoynahanM Jasin
Jun 26, 2003·The Journal of Biological Chemistry·Kuniyoshi IwabuchiAidan J Doherty
Apr 1, 2004·Molecular Cell·Trina GhoshBrenda A Peculis
Jul 21, 2006·Acta Crystallographica. Section D, Biological Crystallography·Wladek MinorMaksymilian Chruszcz
Jun 15, 2007·The Journal of Biological Chemistry·Brenda A PeculisMegan Cleland
Jul 5, 2008·Nature Protocols·Gerrit LangerAnastassis Perrakis
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Apr 13, 2010·Acta Crystallographica. Section D, Biological Crystallography·P EmsleyK Cowtan
Jun 15, 2011·FEBS Letters·Simon Bekker-Jensen, Niels Mailand
Nov 29, 2011·Nature Structural & Molecular Biology·Klara AcsNico P Dantuma
Mar 1, 2012·The EMBO Journal·Frédérick A MalletteStéphane Richard
Jun 14, 2013·Nature·Amélie Fradet-TurcotteDaniel Durocher
Dec 12, 2013·Nature Reviews. Molecular Cell Biology·Stephanie Panier, Simon J Boulton
Jan 29, 2014·Molecular and Cellular Biology·James M Daley, Patrick Sung
Jul 23, 2014·Proceedings of the National Academy of Sciences of the United States of America·Simon M CarrNicholas B La Thangue
Mar 20, 2015·The Biochemical Journal·Luca PalazzoIvan Ahel
Jul 28, 2016·Nature·Marcus D WilsonDaniel Durocher
Feb 28, 2017·Nature·Pascal DranéDipanjan Chowdhury
Jun 22, 2017·Cell Cycle·Pascal Drané, Dipanjan Chowdhury

❮ Previous
Next ❯

Citations

Sep 28, 2018·Nucleic Acids Research·Rosario AvolioDanilo S Matassa
Feb 28, 2019·Nucleic Acids Research·Naike Salvador MorenoPierre-Alexandre Vidi
Feb 10, 2020·Molecular Biology Reports·A A AnuchinaS A Smirnikhina
Aug 9, 2020·Nature Reviews. Genetics·Dali ZongAndré Nussenzweig
Jan 16, 2021·Journal of Zhejiang University. Science. B·Fan Zhang, Zihua Gong
May 8, 2021·Molecular Cell·Nishita ParnandiDipanjan Chowdhury

❮ Previous
Next ❯

Methods Mentioned

BETA
X-ray
pull-down
co-IP
NMR
PCR

Software Mentioned

COOT
Phaser
cellSens standard
PHENIX
PyMol
ARP
3000
wARP
HKL

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.